This SBIR Phase I project will create and validate a combinatorial panel of rats designed to detect genetic differences to drug response including toxicity. The genome sequencing projects are bringing new molecular tools to both the pharmacologist and toxicologist. However, each species has its own biological foundations that may lead to misclassification on drug toxicity and result in (1) a high failure rate of new compounds late in clinical trials, (2) unnecessary exposure to human subjects, and (3) the inability to detect small subsets of at-risk individuals in heterogeneous human populations. A need exists for animal model systems that reflect the heterogeneity of the human population while maintaining the phenotypic accuracy of an inbred strain. PhysioGenix, Inc. will determine whether new combinatorial panel of rats fulfills these requirements by measuring both the biochemical and genetic effects of two compounds with well-known toxicity profiles. The molecular basis for the variable drug response will be characterized by gene expression profiling utilizing DNA microarray technology. Phase II efforts will expand the test compounds and tissues used, leading to construction of a database knowledge warehouse. PROPOSED COMMERCIAL APPLICATIONS: About $500 million is spent annually to purchase rats for drug discovery and safety testing. Service-based and Pharmaceutical companies will integrate PhysioGenix' combinatorial rat panel into their pre-clinical drug toxicity studies. Research programs directed at either rescuing previously failed drugs or rationally deriving new compounds will incorporate PhysioGenix tools into their study designs.